MYO15A

Summary

MYO15A (myosin XVA, HGNC:7594) is a protein-coding gene on chromosome 17p11.2, encoding Unconventional myosin-XV (Q9UKN7). Myosins are actin-based motor molecules with ATPase activity.

This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined.

Source: NCBI Gene 51168 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 3,843 total — 390 pathogenic, 246 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_016239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7594
Approved symbol	MYO15A
Name	myosin XVA
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000091536
Ensembl biotype	protein_coding
OMIM	602666
Entrez	51168

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 retained_intron, 7 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000412324, ENST00000418233, ENST00000433411, ENST00000445289, ENST00000473013, ENST00000536811, ENST00000556535, ENST00000557190, ENST00000557655, ENST00000578472, ENST00000578575, ENST00000578999, ENST00000579848, ENST00000583079, ENST00000585180, ENST00000642418, ENST00000643693, ENST00000644795, ENST00000646238, ENST00000646782, ENST00000647165, ENST00000651088, ENST00000651214

RefSeq mRNA: 1 — MANE Select: NM_016239 NM_016239

CCDS: CCDS42271

Canonical transcript exons

ENST00000647165 — 66 exons

Exon	Start	End
ENSE00000880921	18131239	18131342
ENSE00001593595	18151110	18151290
ENSE00001595443	18127075	18127165
ENSE00001596003	18140517	18140665
ENSE00001603307	18138811	18138936
ENSE00001603544	18149486	18149580
ENSE00001603652	18142079	18142254
ENSE00001614076	18143870	18144000
ENSE00001614675	18148496	18148568
ENSE00001619957	18152112	18152184
ENSE00001621193	18145872	18146107
ENSE00001635575	18153775	18153896
ENSE00001646230	18151846	18151951
ENSE00001649274	18124483	18124565
ENSE00001653227	18126791	18126865
ENSE00001653427	18132453	18132566
ENSE00001654587	18138115	18138246
ENSE00001655965	18125168	18125231
ENSE00001659848	18136563	18136686
ENSE00001662786	18135711	18135824
ENSE00001667009	18150429	18150543
ENSE00001668717	18131468	18131531
ENSE00001702139	18144497	18144592
ENSE00001735906	18136417	18136475
ENSE00001739794	18126347	18126456
ENSE00001741655	18150698	18150765
ENSE00001751160	18137584	18137679
ENSE00001752391	18149216	18149376
ENSE00001754876	18133225	18133386
ENSE00001759273	18151395	18151527
ENSE00001759919	18143566	18143619
ENSE00001777949	18157156	18157230
ENSE00001783228	18150836	18150913
ENSE00001784727	18142756	18142840
ENSE00001797737	18143715	18143796
ENSE00002311321	18118582	18122409
ENSE00002358828	18130805	18130810
ENSE00002905948	18159606	18159679
ENSE00003482535	18162585	18162679
ENSE00003482932	18163742	18163838
ENSE00003489753	18139534	18139611
ENSE00003492664	18178769	18179800
ENSE00003493175	18163244	18163321
ENSE00003502258	18161317	18161447
ENSE00003506266	18158925	18158997
ENSE00003506490	18159935	18160017
ENSE00003509300	18140787	18140832
ENSE00003516441	18173781	18173921
ENSE00003519393	18167590	18167723
ENSE00003519478	18148761	18148952
ENSE00003521694	18156195	18156336
ENSE00003532637	18155314	18155432
ENSE00003534008	18155110	18155225
ENSE00003543946	18141653	18141770
ENSE00003567571	18171638	18171771
ENSE00003583523	18166361	18166521
ENSE00003590328	18156954	18157065
ENSE00003617139	18159275	18159347
ENSE00003621139	18157722	18157900
ENSE00003659024	18141019	18141143
ENSE00003659552	18172157	18172290
ENSE00003660267	18154680	18154755
ENSE00003661267	18158523	18158638
ENSE00003683712	18154131	18154190
ENSE00003688230	18148029	18148210
ENSE00003824350	18108756	18108824

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 95.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5518 / max 472.3001, expressed in 16 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159785	0.2723	6
159784	0.1538	8
159786	0.1257	10

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	95.50	gold quality
adenohypophysis	UBERON:0002196	94.42	gold quality
left testis	UBERON:0004533	84.57	gold quality
right testis	UBERON:0004534	83.95	gold quality
testis	UBERON:0000473	80.72	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.28	gold quality
cerebellar hemisphere	UBERON:0002245	79.32	gold quality
cerebellar cortex	UBERON:0002129	79.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.99	gold quality
right frontal lobe	UBERON:0002810	78.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.42	gold quality
cortical plate	UBERON:0005343	77.14	gold quality
cerebellum	UBERON:0002037	76.76	gold quality
left ovary	UBERON:0002119	75.30	gold quality
sural nerve	UBERON:0015488	75.08	gold quality
right ovary	UBERON:0002118	74.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.10	gold quality
prefrontal cortex	UBERON:0000451	73.44	gold quality
right lobe of liver	UBERON:0001114	72.74	gold quality
anterior cingulate cortex	UBERON:0009835	72.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	72.08	gold quality
cingulate cortex	UBERON:0003027	72.01	gold quality
stromal cell of endometrium	CL:0002255	71.66	gold quality
body of uterus	UBERON:0009853	71.51	gold quality
frontal cortex	UBERON:0001870	71.22	gold quality
neocortex	UBERON:0001950	71.21	gold quality
ganglionic eminence	UBERON:0004023	70.96	gold quality
right uterine tube	UBERON:0001302	70.94	gold quality
tibial nerve	UBERON:0001323	70.49	gold quality
hypothalamus	UBERON:0001898	70.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.83
E-MTAB-5061	no	2.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

71 targeting MYO15A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• myosin XVA protein and mRNA are widely distributed in endocrine cells of the gut and pancreas (PMID:12114748)
• the large N-terminal extension of myosin XVA is required for hearing (PMID:17546645)
• The motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain. (PMID:17853461)
• These are the first MYO15A mutations reported to cause DFNB3 sensorineural hearing loss in the Iranian population. (PMID:19274735)
• Sequencing of MYO15A identified two novel homozygous mutations: a nonsense (c.4998C>A (p.C1666X) in exon 17 and a splice site mutation in intron 54 (c.9229 + 1G>A). A novel mutation of unknown significance, c.7395 + 3G>C, was also identified. (PMID:19309289)
• Estimation of the prevalence of homozygous MYO15A mutations in autosomal recessive nonsyndromic deafness in Turkey as 0.062 (95% confidence interval is 0.020-0.105). (PMID:20642360)
• the second exon of MYO15A from the DNA of all affected individuals ofHEARING LOSS IN A family revealed a duplication of Cytosine in a stretch of seven repetitive C nucleotides (c.1185dupC). (PMID:22245518)
• sequencing of the MYO15A gene led to identification of 7 previously unreported mutations, including 4 missense mutations, 1 nonsense mutation, and 2 deletions in different regions of the myosin-XV protein (PMID:22736430)
• study found two novel compound heterozygous mutations of MYO15A and 13 nonsynonymous variants in the coding exons of MYO15A from Korean exomes in families with autosomal recessive nonsyndromic hearing loss (PMID:23865914)
• Data indicate nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. (PMID:24105371)
• MYO15A c.IVS25+3G>A and c.8375 T>C (p.V2792A) as the autosomal recessive hearing loss-causing mutations (PMID:24206587)
• Mutations in the MYO15A gene are a notable cause of nonsyndromic hearing loss. (PMID:25792667)
• MYO15A mutations that affect domains other than the N-terminal domain, lead to profound sensorineural hearing loss throughout all frequencies. (PMID:26242193)
• MYO15A Mutation is associated with Autosomal Recessive Nonsyndromic Hearing Loss. (PMID:26308726)
• Mutations in exon 2 of MYO15A may cause a less severe phenotype, facilitating the rapid identification of mutations in exon 2 among the 66 exons when linkage of less severe hearing loss to DFNB3 is detected (PMID:26810297)
• MYO15A mutation was corrected by CRISPR/Cas9 system in the iPSCs and rescued the morphology and function of the derived hair cell-like cells. (PMID:26915297)
• Study reports 14 novel recessive mutations in MYO15A that might be a deafness-causing mutations. Also, in the inner ear, myosin 15 seems to be necessary both for the development and the long-term maintenance of stereocilia. (PMID:27375115)
• Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of genetic hearing loss in Oman. (PMID:27734841)
• There are more than 39 deafness genes reported to cause non-syndromic hereditary hearing loss (HHL) in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. [review] (PMID:27743438)
• The MYO15A variant is a common cause of hearing loss in a northeastern Brazilian town. (PMID:27870113)
• novel homozygous donor splice site mutation, c.4596 + 1G > A (IVS12 + 1G > A) was found in MYO15A gene (PMID:28390610)
• We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. (PMID:28964305)
• Some recessive MYO15A variants can cause postlingual onset of progressive partial deafness. (PMID:29482514)
• Six novel MYO15 mutations were identified in a family with nonsyndromic hearing loss. (PMID:29692870)
• Study identified three novel mutations in MYO15A gene causing autosomal recessive nonsyndromic hearing loss in a Chinese family. (PMID:29849560)
• The hearing loss in this case was caused by novel, compound heterozygous mutations in MYO15A. (PMID:30068307)
• In the current study, WES revealed three novel mutations in Myo15 as the underlying cause of prelingual hearing loss observed in three Iranian families. (PMID:30579064)
• A novel nonsense variant of MYO15A was discovered in a consanguineous Iranian family with sensorineural deafness. (PMID:30943474)
• work extended the MYO15A variant spectrum, enriched our knowledge of auditory phenotypes, and tried to explore the genotype-phenotype correlation in different populations in order to investigate the cause of the complex MYO15A genotype-phenotype correlation (PMID:30953472)
• Novel compound heterozygosity at the MYO15A including an duplication variant c.3866dupC, p.His1290Alafs*25 and a 3-bp deletion (c.10251_10253del, p.Phe3420del), resulting in protein length changes and premature protein truncation, respectively, was found in Chinese family with non-syndromic hearing loss. (PMID:31250571)
• Identified a novel homozygous mutation p.R3191C in MYO15A gene causing deafness in Kuzakh family. (PMID:31301639)
• The allele frequencies of mutations in deafness genes in the Taiwanese families are shown. The most prevalent pathogenic variants included GJB2 mutations (22.92%), SLC26A4 mutations (6.03%), OTOF mutations (4.62%), MYO15A mutations (2.98%), and the m.1555A>G mutation (1.95%). (PMID:31581539)
• A novel MITF mutation along with a previously described MYO15A mutation segregate with an autosomal recessive non-syndromic Hearing loss (HL) case with a post-lingual onset. The findings highlight the importance of carrying whole exome sequencing for a comprehensive assessment of HL genetic heterogeneity (PMID:31898538)
• Investigation of MYO15A and MYO7A Mutations in Iranian Patients with Nonsyndromic Hearing Loss. (PMID:31997689)
• Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families. (PMID:32802042)
• [Analysis of MYO15A variation in children with DFNB3]. (PMID:32987461)
• Whole exome sequencing reveals pathogenic variants in MYO3A, MYO15A and COL9A3 and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon. (PMID:33078831)
• Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees. (PMID:33208113)
• The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness. (PMID:33372036)
• A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing. (PMID:33398081)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	myo15aa	ENSDARG00000075292
danio_rerio	myo15ab	ENSDARG00000078474
mus_musculus	Myo15a	ENSMUSG00000042678
rattus_norvegicus	Myo15a	ENSRNOG00000059219
drosophila_melanogaster	Myo10A	FBGN0263705

Paralogs (44): MYH13 (ENSG00000006788), MYO16 (ENSG00000041515), MYO9A (ENSG00000066933), MYO3B (ENSG00000071909), MYH7B (ENSG00000078814), MYH7 (ENSG00000092054), MYO3A (ENSG00000095777), MYO9B (ENSG00000099331), MYH9 (ENSG00000100345), MYH14 (ENSG00000105357), MYH1 (ENSG00000109061), MYH3 (ENSG00000109063), MYH2 (ENSG00000125414), MYO1B (ENSG00000128641), MYO5C (ENSG00000128833), CGNL1 (ENSG00000128849), MYH8 (ENSG00000133020), MYH10 (ENSG00000133026), MYH11 (ENSG00000133392), MYO18B (ENSG00000133454), CCDC102A (ENSG00000135736), MYO1G (ENSG00000136286), MYO7A (ENSG00000137474), MYO1F (ENSG00000142347), CGN (ENSG00000143375), TMF1 (ENSG00000144747), MYH15 (ENSG00000144821), MYO10 (ENSG00000145555), CCDC102B (ENSG00000150636), MYO1E (ENSG00000157483), CCDC158 (ENSG00000163749), MYO1A (ENSG00000166866), MYO5B (ENSG00000167306), MYO7B (ENSG00000169994), MYO1H (ENSG00000174527), MYO1D (ENSG00000176658), MYO18A (ENSG00000196535), MYO6 (ENSG00000196586), MYO5A (ENSG00000197535), MYH6 (ENSG00000197616)

Protein

Protein identifiers

Unconventional myosin-XV — Q9UKN7 (reviewed: Q9UKN7)

Alternative names: Unconventional myosin-15

All UniProt accessions (8): Q9UKN7, A0A2R8Y712, A0A494C1B3, G3V4G3, G3V4Q3, K7EL45, K7EMS7, K7EQV1

UniProt curated annotations — full annotation on UniProt →

Function. Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Required for the arrangement of stereocilia in mature hair bundles.

Subunit / interactions. Interacts with the third PDZ domain of WHRN which is necessary for localization of WHRN to stereocilium tips. Interacts with EPS8. Interacts with FASLG.

Subcellular location. Cell projection. Stereocilium. Cytoplasm. Cytoskeleton.

Tissue specificity. Highly expressed in pituitary. Also expressed at lower levels in adult brain, kidney, liver, lung, pancreas, placenta and skeletal muscle. Not expressed in brain. In the pituitary, highly expressed in anterior gland cells.

Disease relevance. Deafness, autosomal recessive, 3 (DFNB3) [MIM:600316] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKN7-1	1	yes
Q9UKN7-2	2

RefSeq proteins (1): NP_057323* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR000299	FERM_domain	Domain
IPR000857	MyTH4_dom	Domain
IPR001452	SH3_domain	Domain
IPR001609	Myosin_head_motor_dom-like	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036057	MYSc_Myo15	Domain
IPR036961	Kinesin_motor_dom_sf	Homologous_superfamily
IPR038185	MyTH4_dom_sf	Homologous_superfamily
IPR041795	MyoXV_FERM_C	Domain
IPR051567	Unconventional_Myosin_ATPase	Family
IPR059004	MYO15	Domain

Pfam: PF00063, PF00373, PF00612, PF00784, PF07653, PF26570

UniProt features (48 total): region of interest 10, compositionally biased region 10, sequence variant 10, domain 8, sequence conflict 4, splice variant 2, chain 1, coiled-coil region 1, binding site 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6KZ1	X-RAY DIFFRACTION	1.69

Predicted structure (AlphaFold)

No AlphaFold model available for Q9UKN7 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 1315–1322

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 99 (showing top): YAATNRNNNYNATT_UNKNOWN, GOBP_BEHAVIOR, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_VESICLE_MEDIATED_TRANSPORT, AP2_Q3, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, MODULE_285, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOMF_CYTOSKELETAL_MOTOR_ACTIVITY, GOBP_RESPONSE_TO_RADIATION, GOBP_EAR_MORPHOGENESIS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_SENSORY_PERCEPTION

GO Biological Process (6): endocytosis (GO:0006897), actin filament organization (GO:0007015), sensory perception of sound (GO:0007605), locomotory behavior (GO:0007626), response to light stimulus (GO:0009416), inner ear morphogenesis (GO:0042472)

GO Molecular Function (8): microfilament motor activity (GO:0000146), calmodulin binding (GO:0005516), ATP binding (GO:0005524), actin filament binding (GO:0051015), nucleotide binding (GO:0000166), cytoskeletal motor activity (GO:0003774), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), actin cytoskeleton (GO:0015629), membrane (GO:0016020), myosin complex (GO:0016459), stereocilium (GO:0032420), extracellular exosome (GO:0070062), actin-based cell projection (GO:0098858), cytoskeleton (GO:0005856), stereocilium bundle (GO:0032421), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	2
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
actin cytoskeleton	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
sensory perception of mechanical stimulus	1
behavior	1
response to radiation	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
ATP-dependent activity	1
protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
actin binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
cytoskeleton	1
protein-containing complex	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
extracellular vesicle	1
plasma membrane bounded cell projection	1
intracellular membraneless organelle	1
stereocilium	1
cluster of actin-based cell projections	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYO15A	WHRN	Q9P202	998
MYO15A	EPS8	Q12929	955
MYO15A	GJB2	P29033	913
MYO15A	OTOF	Q9HC10	878
MYO15A	GJB6	O95452	866
MYO15A	TMC1	Q8TDI8	853
MYO15A	E9PNW1	E9PNW1	843
MYO15A	ESPN	B1AK53	841
MYO15A	USH1G	Q495M9	827
MYO15A	CDH23	Q9H251	825
MYO15A	SLC26A4	O43511	825
MYO15A	ADGRV1	Q8WXG9	824
MYO15A	USH2A	O75445	814
MYO15A	EPS8L2	Q9H6S3	813
MYO15A	TMPRSS3	P57727	773

IntAct

6 interactions, top by confidence:

A	B	Type	Score
HSF4	HSF1	psi-mi:“MI:0914”(association)	0.530
MYO15A	FASLG	psi-mi:“MI:0407”(direct interaction)	0.440
JAZF1	TNPO2	psi-mi:“MI:0914”(association)	0.350
EPS8	MYO15A	psi-mi:“MI:0915”(physical association)	0.000
USP13	MYO15A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): MYO15A (Proximity Label-MS), MYO15A (Two-hybrid), MYO15A (Two-hybrid), MYO15A (Affinity Capture-MS), MYO15A (Cross-Linking-MS (XL-MS)), P4HB (Cross-Linking-MS (XL-MS)), MYO15A (Cross-Linking-MS (XL-MS)), MYO15A (Affinity Capture-MS), MYO15A (Cross-Linking-MS (XL-MS)), MYO15A (Cross-Linking-MS (XL-MS)), MYO15A (Affinity Capture-MS), MYO15A (Proximity Label-MS), MYO15A (Proximity Label-MS), MYO15A (Proximity Label-MS), MYO15A (Proximity Label-MS)

ESM2 similar proteins: A1A5P0, A2A884, A8WFF7, B7Z0W9, E9PYH6, O15047, O35147, O55189, P03186, P03204, P03267, P09310, P0C724, P24938, P30117, P36717, Q00900, Q0P670, Q1HVH9, Q1LY77, Q28989, Q2T9P9, Q3KSS1, Q3KST0, Q3KSU8, Q53QW1, Q5T1R4, Q61337, Q62840, Q66619, Q66J90, Q69140, Q6AY45, Q76IQ7, Q80U49, Q8AZM1, Q8CDR2, Q8CFT2, Q8CGW4, Q8V7J1

Diamond homologs: A0MP03, A1C4A5, A1DBH2, A2R5J1, A3LYL7, A4RE77, A5DKH0, A5E4A8, A5PF48, A6SED8, A6ZMG6, A6ZZJ1, A7EK16, A7TDZ8, A8N2Y6, A8PWF6, B0CRJ3, B0I1T2, B0Y9Q4, E7F9L8, E9Q634, F1PRN2, F4HWY6, F4HXP9, F4I5Q6, F4IRU3, F4IUG9, F4IVR7, F4JM19, F4K5J1, O00159, O00160, O43795, O88329, O94832, P05659, P08799, P0CP00, P0CP01, P10568

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3843 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	390
Likely pathogenic	246
Uncertain significance	1018
Likely benign	1596
Benign	116

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068743	NM_016239.4(MYO15A):c.7015del (p.Glu2339fs)	Pathogenic
1070174	NM_016239.4(MYO15A):c.4821C>A (p.Tyr1607Ter)	Pathogenic
1072412	NM_016239.4(MYO15A):c.8940dup (p.Ala2981fs)	Pathogenic
1177379	NM_016239.4(MYO15A):c.8730C>A (p.Cys2910Ter)	Pathogenic
1180637	NM_016239.4(MYO15A):c.4142+1G>T	Pathogenic
1180761	NM_016239.4(MYO15A):c.9355A>T (p.Lys3119Ter)	Pathogenic
1185078	NM_016239.4(MYO15A):c.7711_7712dup (p.Gln2571fs)	Pathogenic
1185606	NM_016239.4(MYO15A):c.6551_6552del (p.Cys2184fs)	Pathogenic
1185617	NM_016239.4(MYO15A):c.10538_10544del (p.Leu3513fs)	Pathogenic
1185619	NM_016239.4(MYO15A):c.4596+2_4596+3del	Pathogenic
1185620	NM_016239.4(MYO15A):c.10419_10423del (p.Ser3474fs)	Pathogenic
1185623	NM_016239.4(MYO15A):c.3693-2A>G	Pathogenic
1185628	NM_016239.4(MYO15A):c.6898A>T (p.Lys2300Ter)	Pathogenic
1185647	NM_016239.4(MYO15A):c.212del (p.Lys71fs)	Pathogenic
1185648	NM_016239.4(MYO15A):c.9941del (p.Tyr3314fs)	Pathogenic
1185655	NM_016239.4(MYO15A):c.2266_2272dup (p.Pro758fs)	Pathogenic
1185659	NM_016239.4(MYO15A):c.7654+1G>A	Pathogenic
1185677	NM_016239.4(MYO15A):c.5193_5194insACAG (p.Val1732fs)	Pathogenic
1185683	NM_016239.4(MYO15A):c.1661del (p.Gly554fs)	Pathogenic
1194323	NM_016239.4(MYO15A):c.4602_4603del (p.Met1535fs)	Pathogenic
1197880	NM_016239.4(MYO15A):c.8065del (p.Trp2689fs)	Pathogenic
1208195	NM_016239.4(MYO15A):c.3756+1G>A	Pathogenic
1223726	NM_016239.4(MYO15A):c.8019del (p.His2674fs)	Pathogenic
1297080	NM_016239.4(MYO15A):c.9690+1G>A	Pathogenic
1297083	NM_016239.4(MYO15A):c.5835T>G (p.Tyr1945Ter)	Pathogenic
1298695	NM_016239.4(MYO15A):c.8548C>T (p.Arg2850Ter)	Pathogenic
1301911	NM_016239.4(MYO15A):c.9942_9943delinsTGTGTG (p.Asn3315delinsValTer)	Pathogenic
1301912	NM_016239.4(MYO15A):c.1201del (p.Tyr401fs)	Pathogenic
1301914	NM_016239.4(MYO15A):c.201_202del (p.Gln68fs)	Pathogenic
1301916	NM_016239.4(MYO15A):c.2958del (p.Arg987fs)	Pathogenic

SpliceAI

11665 predictions. Top by Δscore:

Variant	Effect	Δscore
17:18124478:CACA:C	acceptor_loss	1.0000
17:18124479:ACAGA:A	acceptor_loss	1.0000
17:18124480:C:G	acceptor_gain	1.0000
17:18124480:CA:C	acceptor_loss	1.0000
17:18124481:A:AG	acceptor_gain	1.0000
17:18124481:A:AT	acceptor_loss	1.0000
17:18124482:G:C	acceptor_loss	1.0000
17:18124482:G:GG	acceptor_gain	1.0000
17:18124482:GAT:G	acceptor_gain	1.0000
17:18124482:GATGC:G	acceptor_gain	1.0000
17:18124563:GGA:G	donor_gain	1.0000
17:18124564:GA:G	donor_gain	1.0000
17:18124564:GAG:G	donor_gain	1.0000
17:18124566:G:GG	donor_gain	1.0000
17:18125163:TCTA:T	acceptor_loss	1.0000
17:18125166:A:AG	acceptor_gain	1.0000
17:18125167:G:GA	acceptor_gain	1.0000
17:18125167:GA:G	acceptor_gain	1.0000
17:18125167:GAGA:G	acceptor_gain	1.0000
17:18125167:GAGAC:G	acceptor_gain	1.0000
17:18125232:G:GG	donor_gain	1.0000
17:18126457:G:GG	donor_gain	1.0000
17:18127073:A:AG	acceptor_gain	1.0000
17:18127074:G:GG	acceptor_gain	1.0000
17:18131229:T:TA	acceptor_gain	1.0000
17:18131341:GG:G	donor_gain	1.0000
17:18131342:GG:G	donor_gain	1.0000
17:18132565:AGGTG:A	donor_loss	1.0000
17:18132567:GT:G	donor_loss	1.0000
17:18132568:T:A	donor_loss	1.0000

AlphaMissense

22872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:18131518:G:C	R1398T	1.000
17:18131518:G:T	R1398M	1.000
17:18127095:A:T	K1321I	0.999
17:18131508:G:A	E1395K	0.999
17:18131509:A:T	E1395V	0.999
17:18131517:A:G	R1398G	0.999
17:18131519:G:C	R1398S	0.999
17:18131519:G:T	R1398S	0.999
17:18132470:T:A	N1408K	0.999
17:18132470:T:G	N1408K	0.999
17:18133352:T:C	L1483P	0.999
17:18133360:G:C	G1486R	0.999
17:18133361:G:A	G1486D	0.999
17:18133361:G:T	G1486V	0.999
17:18137598:C:A	N1598K	0.999
17:18137598:C:G	N1598K	0.999
17:18137612:T:C	L1603P	0.999
17:18137622:C:A	N1606K	0.999
17:18137622:C:G	N1606K	0.999
17:18138221:T:A	L1661H	0.999
17:18138221:T:C	L1661P	0.999
17:18138830:T:C	L1676P	0.999
17:18138838:T:C	C1679R	0.999
17:18138899:T:C	F1699S	0.999
17:18138931:T:G	Y1710D	0.999
17:18139557:C:A	N1719K	0.999
17:18139557:C:G	N1719K	0.999
17:18127082:A:C	S1317R	0.998
17:18127084:C:A	S1317R	0.998
17:18127084:C:G	S1317R	0.998

dbSNP variants (sampled 300 via entrez): RS1000017330 (17:18121311 C>T), RS1000020962 (17:18117014 T>C,G), RS1000049878 (17:18171485 C>T), RS1000138340 (17:18165001 T>C), RS1000192619 (17:18153460 G>A,T), RS1000211270 (17:18146789 G>A), RS1000305874 (17:18147011 G>C,T), RS1000369066 (17:18140756 C>T), RS1000378208 (17:18134548 C>A,T), RS1000386889 (17:18139671 C>A,T), RS1000399463 (17:18133660 C>G,T), RS1000453060 (17:18128675 G>A), RS1000474468 (17:18127547 G>A), RS1000554117 (17:18161072 G>A), RS1000603760 (17:18138019 T>C)

Disease associations

OMIM: gene MIM:602666 | disease phenotypes: MIM:600316, MIM:301050, MIM:220290, MIM:607197, MIM:128600, MIM:601071, MIM:160980

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 3	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (11): autosomal recessive nonsyndromic hearing loss 3 (MONDO:0010860), hearing loss disorder (MONDO:0005365), Alport syndrome (MONDO:0018965), hearing loss, autosomal recessive (MONDO:0019588), ear malformation (MONDO:0007500), intellectual disability (MONDO:0001071), nonsyndromic genetic hearing loss (MONDO:0019497), sensorineural hearing loss disorder (MONDO:0020678), autosomal recessive nonsyndromic hearing loss 9 (MONDO:0010986), congenital portosystemic shunt (MONDO:0018811), Carney complex, type 1 (MONDO:0008057)

Orphanet (8): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Alport syndrome (Orphanet:63), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884), Congenital portosystemic shunt (Orphanet:480531), Carney complex (Orphanet:1359), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

3 total (4 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003577	Congenital onset
HP:0011476	Profound sensorineural hearing impairment
HP:0000407	Sensorineural hearing impairment

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001762_847	Obesity-related traits	4.000000e-06
GCST002539_86	Schizophrenia	2.000000e-08
GCST006137_10	Serum folate levels	8.000000e-06
GCST008497_2	Change in neurofilament light levels	1.000000e-06
GCST90002390_104	Mean corpuscular hemoglobin	3.000000e-12
GCST90002392_8	Mean corpuscular volume	1.000000e-10
GCST90002403_352	Red blood cell count	1.000000e-10
GCST90013410_58	Basal cell carcinoma	2.000000e-08
GCST90014033_69	Haemorrhoidal disease	1.000000e-08
GCST90020025_1404	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020025_1406	Waist-to-hip ratio adjusted for BMI	2.000000e-11
GCST90020026_433	Hip index	3.000000e-09
GCST90020026_434	Hip index	8.000000e-09
GCST90020027_31	Waist-hip index	2.000000e-09
GCST90020027_32	Waist-hip index	1.000000e-08
GCST90020027_34	Waist-hip index	6.000000e-12
GCST90020027_454	Waist-hip index	3.000000e-08
GCST90020029_585	Waist circumference adjusted for body mass index	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004908	testosterone measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564609	Deafness, Autosomal Recessive (supp.)
C563961	Deafness, Autosomal Recessive 3 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295979 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
licochalcone B	increases expression	1
bisphenol S	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Formaldehyde	increases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Genistein	decreases expression, increases reaction	1
Acrylamide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4155514	Binding	Inhibition of human myosin 15 by NADH-coupled spectrophotometric analysis	Medicinal Chemistry and Use of Myosin II Inhibitor ( S)-Blebbistatin and Its Derivatives. — J Med Chem

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound